Oxazaphosphorins belong to the group of alkylating cytostatic agents employed in the treatment of tumour diseases.
Therapeutic administration of oxazaphosphorins typically is by means of peroral and parenteral formulations. The major proportion of parenteral applications is carried out by way of infusions. As a result of the limited stability of oxazaphosphorins in aqueous solution, ready-to-use injectable solutions which can be stored have not been known until now. Parenteral formulations as of the present time tend to consist of injection vials which contain the differing doses of active ingredients in dry substance form, from which the injectable solution is prepared just before administration.
In the case of an oxazaphosphorin such as cyclophosphamide, the dry substance for parenteral application may, for example, consist of a pathogen-free mixture of crystalline cyclophosphamide monohydrate and salt. There are, however, considerable disadvantages associated with the use of such a pathogen-free crystalline mixture as compared with a ready-to-use injectable solution. Thus, even during preparation of the active ingredient, for example on crystallization, during centrifuging of the crystals, during drying, grinding and mixing with the sterile salt, which is also laborious to prepare, it is necessary to work under sterile and aseptic conditions. Finally, the finished mixture must be filled under sterile conditions. There is a always a danger of contamination by particles or microbes during this laborious procedure.
In addition, even if every care is taken during preparation, one cannot avoid the formation of differently sized crystals, so that the preparation of cyclophosphamide solutions using dry substance in injection vials is a very time-consuming procedure. In particular, in clinics and hospitals this involves the nursing staff in additional effort which is no longer warranted.
Furthermore, the exposure of the nursing staff in the course of their work, during the making-up of solutions of potentially carcinogenic cytostatic agents should be taken into consideration and contamination of the nursing staff should therefore be avoided as far as possible. During the preparation of solutions from dry substance it cannot with certainty be excluded that such particles of active ingredient could be inhaled.
For the reasons stated above, there is a need for an oxazaphosphorin formulation for parenteral administration which is easy to handle. Such a formulation should as far as possible rule out any danger for the nursing staff and, last but not least, permit economically priced therapy.
The preparation of directly injectable stable aqueous or water containing oxazaphosphorin solutions is, however, not possible owing to the instability of oxazaphosphorins as a result of hydrolytic decomposition.
It has now surprisingly been found that the non-aqueous solutions of the present invention display excellent stability and are capable of being stored for a long time. The solutions according to the present invention can be diluted in a simple manner for parenteral administration with water, Ringer's solution or similar infusion liquids, whereby the dilution should generally be carried out so that the maximum solvent or ethanol concentration is not above 10%.